8
D. Kaldre et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
8.6 mg of thin film (43%). IR (thin film)
m
3238, 2962, 2933, 2873,
514.3174, found: 514.3182; LRMS (ESI) m/z 516.5 [M+H]+. Purity
>95% LC/MS, tr = 13.00 min (method A).
1655, 1609, 1503, 1275 cmꢀ1
;
1H NMR (500 MHz, CD3OD) d
6.97–6.91 (m, 2H), 66.85 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz,
1H), 6.75 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 4.11 (dd,
J = 10.0, 2.9 Hz, 1H), 3.96 (t, J = 5.8 Hz, 2H), 3.86 (dd, J = 10.0,
7.7 Hz, 1H), 3.61 (dd, J = 7.7, 2.9 Hz, 1H), 2.20–2.13 (m, 5H), 2.10
(s, 3H), 2.03 (q, J = 7.4 Hz, 4H), 1.87–1.75 (m, 4H), 1.00 (s, 9H),
5.11. Ethyl 5-(4-(3-(4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl)-
pentan-3-yl)-2-methylphenoxy)-4-oxopentanoate (11)
Synthesized from 7 according to procedure similar to that for 9b
(alkylating reagent 1.2 equiv of methyl 5-bromo-4-oxopentanoate
at 40 °C for 24 h) in 72% yield as colourless oil: Rf 0.40 (20:80
0.58 (t, J = 7.3 Hz, 6H) ppm; 13C NMR (126 MHz, CD3OD)
d
171.22, 154.80, 154.70, 140.61, 140.45, 130.11, 130.04, 125.73,
125.35, 125.08, 109.76, 109.62, 77.24, 69.48, 66.98, 48.00, 33.66,
32.05, 28.77, 28.56, 25.17, 22.20, 15.38, 15.23, 7.34 ppm; HRMS
(ESI) Calc. for C30H44O5N [M-H]-: 498.3225, found: 498.3232; pur-
ity >95% (LC/MS), tr = 11.10 min (method B).
EtOac/Hex); IR (thin film)
m 2966, 2958, 2877, 1727, 1502,
1220 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.91 (m, 2H), 6.56 (d,
;
J = 8.3 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 4.83 (s, 2H), 4.55 (s, 2H),
4.13 (q, J = 7.1 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 6.5 Hz,
2H), 2.23 (s, 6H), 2.01 (q, J = 7.3 Hz, 4H), 1.41–1.04 (m, 12H), 0.58
(t, J = 7.3 Hz, 6H) ppm; 13C NMR (126 MHz, CDCl3) d 210.04,
206.90, 172.55, 153.98, 153.50, 141.73, 141.34, 130.87, 130.71,
126.20, 126.01, 125.97, 125.60, 110.14, 109.74, 72.93, 69.57,
60.72, 48.42, 43.22, 33.87, 29.23, 27.46, 26.35, 16.66, 16.60,
5.8. N-Hydroxy-6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanamide (10c)
Synthesized from 9c according to procedure similar to that for
14.16, 8.42 ppm; HRMS (ESI) Calc. for
547.3030, found 547.3025.
C
32H44O6Na [M+Na]+:
10b in 29% yield as thin film. IR (thin film)
m 3238, 2961, 2940,
2873, 1654, 1503, 1220 cmꢀ1 1H NMR (500 MHz, CD3OD) d
;
6.97–6.90 (m, 2H), 6.85 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H),
6.74 (dd, J = 8.6 Hz, 2H), 4.11 (dd, J = 10.0, 3.0 Hz, 1H), 3.94 (t,
J = 6.3 Hz, 2H), 3.86 (dd, J = 10.0, 7.8 Hz, 1H), 3.61 (dd, J = 7.7,
2.9 Hz, 1H), 2.15 (s, 3H), 2.12 (t, J = 6.2 Hz, 2H), 2.10 (s, 3H), 2.03
(q, J = 7.2 Hz, 4H), 1.87–1.75 (m, 2H), 1.75–1.63 (m, 2H), 1.60–
1.47 (m, 2H), 0.99 (s, 9H), 0.58 (t, J = 7.3 Hz, 6H) ppm; 13C NMR
(125 MHz, CD3OD) d 171.44, 154.80, 154.77, 140.62, 140.38,
130.12, 130.03, 125.73, 125.4, 125.35, 125.10, 109.78, 109.64,
77.25, 69.50, 67.31, 33.65, 32.34, 28.79, 25.44, 25.16, 25.13,
15.36, 15.23, 7.33 ppm; HRMS (ESI) Calc. for C31H46O5N [MꢀH]ꢀ:
512.3382, found: 512.3377; purity >95% LC/MS, tr = 11.40 min
(method B).
5.12. Methyl 6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methyl-
phenyl)pentan-3-yl)-2-methylbenzamido)hexanoate (13a)
12 (23.0 mg, 0.56 mmol, 1.0 equiv) was dissolved in dichloro-
methane (3 mL) and methyl-7-aminohexanoate hydrochloride
(15.3 mg, 0.084 mmol, 1.50 equiv) was added followed by EDC
HCl (12.8 mmol, 0.067 mmol, 1.2 equiv), DMAP (0.70 mg,
0.0056 mmol, 0.10 equiv) and triethylamine (23.4 ll, 0.168 mmol,
3.0 equiv). Reaction was stirred at ambient temperature for 12 h.
1 M HCl solution (5 mL) was added and resulting mixture was
extracted with ethylacetate (3 ꢁ 5 mL) combined organic layer
were washed with saturate NaCl (5 mL), dried over anhydrous
sodium sulfate, crude product was purified by chromatography
on silica gel eluating 15% ethyl acetate/hexanes to afford 16.8 mg
5.9. N-Hydroxy-7-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl)pentan-3-yl)-2-methylphenoxy)heptanamide (10d)
transparent oil (57%). Rf 0.30 (20:80 EtOac/Hex); IR (thin film)
m
3309, 2935, 2874, 1738, 1639, 1502, 1245 cmꢀ1 1H NMR
;
Synthesized from 9d according to procedure similar to that for
10b in 33% yield as colourless film; 1H NMR (500 MHz, CD3OD) d
6.97–6.91 (m, 2H), 6.85 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H),
6.75 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 4.11 (dd, J = 10.0,
2.9 Hz, 1H), 3.94 (t, J = 6.3 Hz, 2H), 3.86 (dd, J = 10.0, 7.8 Hz, 1H),
3.61 (dd, J = 7.8, 2.9 Hz, 1H), 2.15 (s, 3H), 2.12–2.07 (m, 5H), 2.03
(q, J = 7.3 Hz, 4H), 1.83–1.73 (m, 2H), 1.68–1.61 (m, 2H), 1.57–
1.45 (m, 2H), 1.45–1.36 (m, 2H), 1.00 (s, 9H), 0.58 (t, J = 7.3 Hz,
(400 MHz, CDCl3) d 7.20 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.98 (d,
J = 8.0 Hz, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H),
6.69 (d, J = 8.5 Hz, 1H), 5.73 (t, J = 5.7 Hz, 1H), 4.09 (dd, J = 9.2,
2.6 Hz, 1H), 3.85 (t, J = 8.9 Hz, 1H), 3.66 (dd, J = 8.7, 2.6 Hz, 1H),
3.66 (s, 3H), 3.41 (dd, J = 13.2, 6.9 Hz, 2H), 2.39 (s, 3H), 2.33 (t,
J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.04 (q, J = 7.3 Hz, 4H), 1.75–1.55 (m,
4H), 1.45–1.32 (m, 2H), 1.01 (s, 9H), 0.59 (t, J = 7.3 Hz, 6H) ppm;
13C NMR (75 MHz, CDCl3) d 174.02, 170.35, 154.45, 150.99,
140.35, 135.14, 133.54, 130.66, 130.64, 126.08, 125.65, 125.51,
110.06, 77.26, 69.15, 51.53, 49.04, 39.50, 33.87, 33.55, 29.41,
29.02, 26.42, 26.05, 24.51, 20.15, 16.62, 8.33 ppm; HRMS (ESI)
Calc. for C33H50O5N [M+H]+: 540.3684, found 540.3691.
6H). 13C NMR (125 MHz, CD3OD)
d 154.80, 140.62, 140.35,
130.11, 130.02, 125.72, 125.34, 125.06, 109.74, 109.60, 104.99,
77.2, 69.47, 67.39, 33.66, 29.98, 28.77, 28.49, 25.57, 25.34, 25.16,
15.38, 15.23, 7.33 ppm; HRMS (ESI) Calc. for C32H48O5N [MꢀH]ꢀ:
526.3538, found: 526.3544; purity >95% LC/MS, tr = 13.77 min
(method A).
5.13. Methyl 7-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methyl-
phenyl)pentan-3-yl)-2-methylbenzamido)heptanoate (13b)
5.10. N,4-Dihydroxy-5-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-
3-methylphenyl)pentan-3-yl)-2-methylphenoxy)pentanamide (10e)
Synthesized from 12 according to procedure similar to that for
13a (with 1.50 equiv of methyl-7-aminoheptanoate hydrochloride)
in 81% yield as colourless oil: Rf 0.32 (20:80 EtOac/Hex); IR (thin
Synthesized from 10e according to procedure similar to that for
10b in 52% yield as a colourless film; IR (thin film)
m 3313,2962,
film)
m
3309, 2926, 2857, 1738, 1639, 1608, 1536, 1461,
2929, 2869,1503, 1220 cmꢀ1 1H NMR (400 MHz, CD3OD) d 6.95
;
1246 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.21 (d, J = 8.0 Hz, 1H),
(d, J = 8.5 Hz, 2H), 6.84 (s, 2H), 6.75 (d, J = 8.5 Hz, 2H), 4.11 (dd,
J = 10.0, 2.9 Hz, 1H), 3.96–3.82 (m, 3H), 3.61 (dd, J = 7.8, 2.8 Hz,
1H), 2.36–2.18 (m, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 2.03 (q,
J = 7.2 Hz, 4H), 1.89–1.74 (m, 2H), 1.00 (s, 9H), 0.58 (t, J = 7.3 Hz,
6H) ppm; 13C NMR (75 MHz, CD3OD) d 171.34, 154.82, 154.57,
140.81, 140.57, 130.11, 125.75, 125.71, 125.36, 109.76, 77.24,
71.59, 69.48, 68.99, 48.01, 33.66, 29.30, 28.75, 25.16, 15.38,
7.00 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.85
(d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 5.73 (t, J = 5.7 Hz, 1H),
4.09 (dd, J = 9.2, 2.6 Hz, 1H), 3.85 (t, J = 8.9 Hz, 1H), 3.70 (dd,
J = 8.7, 2.6 Hz, 1H), 3.66 (s, 3H), 3.41 (dd, J = 13.2, 6.9 Hz, 2H),
2.39 (s, 3H), 2.31 (t, J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.04 (q,
J = 7.3 Hz, 4H), 1.75–1.55 (m, 4H), 1.45–1.32 (m, 4H), 1.01 (s, 9H),
0.59 (t, J = 7.3 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3) d 174.16,
170.34, 154.44, 150.97, 140.36, 135.12, 133.59, 130.64, 126.08,
15.25, 7.33 ppm; HRMS (ESI) Calc. for
C
30H44O6N [M-H]-: